Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate, many of which play a role in normal cell growth. Protein tyrosine kinases (PTKs) play a key role in signal transduction pathways that regulate cell division and differentiation. Certain growth factor receptor kinases have been identified as markers for a poor prognosis in many human cancers if they are overexpressed. See Hickey e al. J. Cancer, 1994, 74:1693.
Similar to PTKs, serine/threonine kinases are also involved in the regulation of cell growth. The MEK kinase Tpl-2 (also known as Cot and MAP3K8) is a serine/threonine kinase that has been shown to be a protooncogene when it is cleaved at its C-terminus. See Beinke et al., Mol. Cell Biol., 2003, 23:4739-4752.
Tpl-2 is known to be upstream in the MEK-ERK pathway and is essential for LPS induced tumor necrosis factor-α (TNF-α) production, as demonstrated by the Tpl2 knockout mouse (Tsichlis et. al. EMBO J., 1996, 15, 817). Tpl-2 is also required for TNF-α signaling (i.e. the cellular response to ligation of the TNF-α receptor). TNF-α is a pro-inflammatory cytokine that is involved in inflammation in a number of disease states, most notably in the autoimmune disease rheumatoid arthritis (RA). A protein therapeutic ENBREL/etanercept (sTNRRα) is currently available to patients with RA. However, an orally available small molecule that inhibits TNF-α synthesis and/or signaling is desirable. Tpl2 is not inhibited by staurosporine and it is the only human kinase that contains a proline instead of a conserved glycine in the glycine-rich ATP binding loop. These unique features of Tpl2 may increase the potential for discovering a selective inhibitor of the enzyme.
Heretofore, there have not been described [1,7]naphthyridines that bind to and inhibit serine/threonine protein kinases and inhibit TNF-α synthesis and/or signaling that are useful in the treatment of inflammatory diseases. The present invention provides 4,6-diamino-[1,7]naphthyridine-3-carbonitriles that are inhibitors of the serine/threonine kinase Tpl-2 and can be used to treat inflammatory diseases, such as RA. The invention also provides methods of making the 4,6-diamino-[1,7]naphthyridine-3-carbonitriles.